A number of epidemiological searches have clarified that hypercholesterolemia, particularly, high level of low density lipoprotein (LDL)-cholesterol in serum, is a risk factor of arteriosclerotic diseases (e.g., cardiac infarction, angina pectoris, cerebral infarction and the like). As a pharmaceutical agent to lower serum LDL-cholesterol, pharmaceutical agents that inhibit 3-hydroxy-3-methylglytaryl coenzyme A (HMG-CoA) reductase have been clinically used, and large scale clinical tests have clarified that they show a certain effect on the decrease of incidence of coronary diseases (N. Engl. J. Med., 34, 498-511 (1999)). However, the effect is not fully satisfactory. In addition, it is epidemiologically known that the concentration of high density lipoprotein (HDL)—cholesterol in serum shows an inverse correlation with the incidence of coronary diseases (N. Engl. J. Med., 321, 1311-1316 (1989), Am. Heart J., 110, 1100-1107 (1985)), and a pharmaceutical agent that increases serum HDL-cholesterol has been drawing attention as a pharmaceutical agent for the prophylaxis or treatment of arteriosclerotic diseases.
The cholesteryl ester transfer protein (CETP) catalyzes transfer of cholesteryl ester from HDL to LDL and very low density lipoprotein (VLDL) (J. Lipid Res., 34, 1255-1274 (1993)), and is deeply involved in the inverse transfer system of cholesterol or transfer of cholesterol from peripheral tissues to the liver. As the inverse transfer system of cholesterol, the following three pathways are known.    (1) Free cholesterol accumulated in the peripheral tissues is extracted by HDL, undergoes the action of lecithin-cholesterol acyltransferase (LCAT) and converted to cholesteryl ester on HDL. The cholesteryl ester on HDL is transferred by CETP to LDL or VLDL in exchange of triglyceride, and cholesterol is transferred to the liver via LDL receptor.    (2) HDL becomes apoprotein E-containing HDL and is uptaken into the liver via LDL receptor.    (3) Cholesteryl ester on HDL is directly uptaken into the liver via HDL receptor.
Because CETP is deeply involved in the cholesterol inverse transfer system, the intensity of its activity in blood is considered to be linked to the control of blood HDL-cholesterol concentration. With regard to the correlation between CETP and blood HDL—cholesterol concentration, for example, the following findings are known. When CETP activity is inhibited by CETP monoclonal antibody in rabbit and hamster, serum HDL—cholesterol concentration increases (J. Clin. Invest., 84, 129-137 (1989), Atherosclerosis, 110, 101-109 (1994)). Transgenic mouse and transgenic rat that expressed CETP shows increased LDL-cholesterol concentration (J. Biol. Chem., 266, 10796-10801 (1991), Nat. Med., 5, 1383-1389 (1999)). From epidemiological search, individuals showing decreased or no CETP activity due to genetic mutation also show increased blood HDL—cholesterol concentration (Nature, 342, 448-451 (1989), Atherosclerosis, 58, 175-186 (1985)).
From the above findings, it is considered that intensity of CETP activity has an inverse correlation with arteriosclerosis-suppressive HDL-cholesterol, and inhibition of CETP activity is expected to lower the risk of progression of coronary diseases. In fact, it is known that CETP activity varies depending on the animal species, and arteriosclerosis is induced by cholesterol loading in animals having high CETP activity (rabbit etc.), but arteriosclerosis is not easily induced in animals free of CETP (rat and the like). When CETP activity was inhibited sustainably in rabbit by administration of antisense RNA, blood HDL-cholesterol concentration increased and the progression of arteriosclerotic lesion was suppressed (J. Biol. Chem., 273, 5033-5036 (1998)). Therefore, a pharmaceutical agent that suppresses CETP activity is expected to act suppressively on arteriosclerotic diseases by inhibiting transfer of cholesterol from HDL to LDL or VLDL, increasing arteriosclerosis-suppressive HDL-cholesterol and simultaneously decreasing arteriosclerosis-promotive VLDL-cholesterol or LDL-cholesterol. That is, a pharmaceutical agent that suppresses CETP activity is expected to give a pharmaceutical agent for the prophylaxis or treatment of the diseases such as acute coronary syndrome, acute cardiac infarction, unstable angina pectoris, PTCA or arterial restenosis after stent placement, peripheral arterial occlusion, hyperlipidemia, cerebral infarction, stroke and the like, or an agent for suppressing progression of focal arteriosclerosis.
The pharmaceutical agents having CETP inhibitory action are disclosed in, for example, WO99/41237, lipids, 29, 811-818 (1994), WO98/35937, Atherosclerosis, 128, 59-66 (1997), Bioorg. Med. Chem. Lett., 6, 919-922 (1996), U.S. Pat. No. 5,925,645, U.S. Pat. No. 5,932,587, Europe patent No. 825185, Europe patent No. 818448, Angew. Chem., Int. Ed., 38, 3373-3375 (1999), WO99/14174, WO00/18724, WO00/17164 and the like.
As the aminoethanol derivatives, for example, JP-A-11-286478 discloses tert-butyl benzyl-[2(S)-hydroxy-2-thiazol-2-yl-1(S)-(4-trifluoromethyl-benzyl)-ethyl]-carbamate as a compound to be a starting material for an antivirus agent, WO99/45928 discloses a compound to be a starting material for a compound having an action of improving autoimmune diseases, JP-A-11-246437 discloses a compound to be a starting material for a compound having a gastrointestinal mucosal protective action, WO98/18794 discloses a compound to be a starting material for a compound having a chymase inhibitory action, Lett. Pept. Sci., 2, 229-232 (1995) discloses a compound to be a starting material for a compound having an HIV-1 protease inhibitory action and a DPP-IV inhibitory action, WO93/25574 discloses a compound to be a starting material for a compound having a angiotensin I chymase inhibitory action, WO89/10752 discloses a compound to be a starting material for a compound having a retroviral protease inhibitory action, EP No. 231919 discloses a compound having a renin inhibitory action, and French Patent No. 1578851 discloses a compound having an adrenergic action, but no disclosure is found that these compounds have a prophylactic or therapeutic action on arteriosclerotic diseases or any description suggestive thereof.
As a pharmaceutical agent that increases plasma HDL-cholesterol (HDL-C), fibrate-type pharmaceutical agents and nicotinic acid have been used. They show an indirect HDL-C increasing action and side effects are a concern. As the situation stands, the development of a novel pharmaceutical agent that directly increases HDL-cholesterol and affords a sufficiently satisfactory effect in the prophylaxis or treatment of arteriosclerotic diseases such as ischemic heart and brain diseases, peripheral arterial occlusion and the like is awaited.